Gastric Cancer: Molecular Characterization, Therapeutic Innovations, and Perspectives

The standard of care for unresectable locally-advanced or metastatic GC is the combination of fluoropyrimidines and platins. The addition of monoclonal antibodies will be based on the expression of biomarkers in the tumor tissue.

Expression of PD-L1 may be measured by the number of PD-L1-stained tumor cells divided by the total number of viable tumor cells and multiplied by 100, which is called tumor proportion score (TPS), or as the total number of lymphocytes, macrophages, and PD-L1-stained tumor cells divided by the total number of viable tumor cells and multiplied by 100, which is called combined positive score (CPS).8 11 Studies on GC have predominantly used the CPS as the main score to measure PD-L1 expression. In the phase-III CheckMate 649 study,8 1,581 previously-untreated, unresectable and HER2-negative patients were randomized to receive nivolumab plus chemotherapy or chemotherapy alone (5-fluorouracil [5-FU] and leucovorin combined with oxaliplatin [FOLFOX] or capecitabine plus oxaliplatin [CAPOX]). Compared to chemotherapy alone, nivolumab plus chemotherapy significantly increased the overall survival (OS) in the whole population (median: 13.8 months versus 11.6 months; hazard ratio [HR]: 0.79; 95% confidence interval [95%CI]: 0.71–0.88) and progression-free survival (PFS) (median: 7.7 months versus 6.9 months; HR: 0.79; 95%CI: 0.70–0.89). In the analysis of OS in the CPS ≥ 5 population, which was the primary endpoint of the study,8 the benefit was even greater, with a median OS of 14.4 months versus 11.1 months (HR: 0.70; 95%CI: 0.61–0.81), and a median PFS of 8.1 months versus 6.1 months (HR: 0.70; 95%CI: 0.60–0.81). Based on the CheckMate 6498 findings, nivolumab was approved by the United States Food and Drug Administration (FDA) and by the Brazilian Health Regulatory Agency (Agência Nacional de Vigilância Sanitária, ANVISA, in Portuguese) for every patient with advanced GC, regardless of the PD-L1 expression. On the other hand, European agencies, and the guidelines of the United States National Comprehensive Cancer Network (NCCN) and of the American Society of Clinical Oncology (ASCO) suggest that the immune checkpoint inhibitor should be added to chemotherapy only in patients with CPS ≥ 5.12 The decision to add nivolumab in patients with CPS between 1 and 4 should be made in a case-by-case basis.

Pembrolizumab associated with oxaliplatin-based chemotherapy is another initial treatment option. In the phase-III KEYNOTE-859 study, with 1,579 HER2-negative patients, the addition of pembrolizumab to chemotherapy improved the median OS (12.9 months versus 11.5 months; HR: 0.78; 95%CI: 0.70–0.87) and PFS (6.9 months versus 5.6 months; HR: 0.76; 95%CI: 0.67–0.85) compared to the arm which received placebo associated with chemotherapy.9 The benefits were consistent across all subgroups, including those with CPS ≥ 1 (HR: 0.74; 95%CI 0.65–0.84 for OS; and HR: 0.72; 95%CI: 0.63–0.82 for PFS), CPS ≥ 10 (HR: 0.65; 95%CI: 0.53–0.79 for OS; and HR: 0.62; 95%CI: 0.51–0.76 for PFS), and those with MSI-H (HR: 0.34; 95%CI: 0.18–0.66 for OS; and HR: 0.27; 95%CI: 0.14–0.53 for PFS). Neither the CheckMate 649 nor the KEYNOTE-859 demonstrated statistically significant benefits in terms of OS in the population of patients with CPS < 1 for PD-L1 expression. Pembrolizumab as a single agent is not recommended based on the results of the KEYNOTE-062 study.13 Among 763 patients with untreated, locally-advanced/unresectable or metastatic gastric/gastroesophageal junction cancer with CPS ≥ 1 for PD-L1 enrolled, pembrolizumab was noninferior to chemotherapy in terms of OS, which was the primary endpoint of the study (median: 10.6 versus 11.1 months; HR: 0.91; 95%CI: 0.69–1.18).13 Pembrolizumab prolonged OS compared to chemotherapy in patients with CPS ≥ 10 (median: 17.4 versus 10.8 months; HR: 0.69; 95%CI: 0.49–0.97), but this difference was not statistically tested.

The addition of trastuzumab to chemotherapy is considered in patients with HER2-positive tumors, which are defined by 3+ immunohistochemistry (IHC) staining or 2+ and positive fluorescent in-situ hybridization (FISH). The addition of pembrolizumab to trastuzumab is also suggested, based on the phase-III KEYNOTE-811 study.14

The benefit of trastuzumab in advanced HER2-positive GC was addressed in the phase-III ToGA trial,7 which compared standard chemotherapy (cisplatin plus infusional 5-FU or capecitabine) with or without trastuzumab. The objective response rate (ORR) and OS were higher with trastuzumab (47% versus 35%; 13.8 months versus 11.1 months; HR: 0.74; 95%CI: 0.60–0.91 respectively). An exploratory analysis of the subgroups defined by HER2 expression showed that trastuzumab was more effective in prolonging survival in individuals with 3+ IHC (HR: 0.66; 95%CI: 0.50–0.87) compared to patients with 2+ IHC (HR: 0.78; 95%CI: 0.55–1.10). The value of adding pembrolizumab to trastuzumab and chemotherapy was confirmed in the multicenter phase-III KEYNOTE-811 study,14 in which 698 patients were randomized to receive pembrolizumab or placebo administered with trastuzumab plus platinum-containing cytotoxic chemotherapy. The ORR was significantly higher with pembrolizumab (73% versus 60%), as well as the rate of complete responses (17% versus 11%). A recently-published interim analysis38 also demonstrated a significant increase in PFS, mainly in PD-L1-positive tumors (CPS ≥ 1), with a median PFS of 10.9 versus 7.3 months (HR: 0.71; 95%CI: 0.59–0.86).

The efficacy and safety of trastuzumab deruxtecan (T-Dxd), an antibody-drug conjugate, were evaluated in patients with HER2-positive GC whose disease progressed after the initial trastuzumab-based therapy.15 16 In a non-randomized phase-II study (DESTINY-Gastric02),16 T-Dxd demonstrated ORR of 42% as second-line therapy. In a randomized trial (DESTINY-Gastric01) evaluating patients whose disease had progressed after two previous therapies,15 which included trastuzumab, fluoropyrimidines, and platins, the subjects were randomized to receive T-Dxd or chemotherapy, and there was an improvement in OS (13.0 months versus 8.0 months) and PFS (5.6 versus 3.5 months). Based on these data, T-Dxd was approved in the United States and Brazil for the treatment of cases of advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma that has experienced disease progression while on trastuzumab.

Regarding bispecific antibodies, zanidatamab, which targets 2 distinct HER2 epitopes, was evaluated in a phase-I study,17 in which this monoclonal antibody was well tolerated and yielded long-lasting responses in pretreated GC patients. In a phase-II study,18 an ORR of 79% was demonstrated with zanidatamab plus chemotherapy. Based on these findings, a phase-III study (HERIZON-GEA-01) (Table 2) was designed to evaluate the efficacy and safety profile of zanidatamab plus chemotherapy with or without tislelizumab, an anti-PD-1 monoclonal immunoglobulin G4 antibody, versus the standard of care (trastuzumab plus chemotherapy) as a first-line treatment for patients with advanced/metastatic HER2-positive gastroesophageal adenocarcinomas (GEAs)39.

In cases of dMMR/MSI-H GEA identified through immunohistochemistry, it is highly recommended that the patients receive immune checkpoint inhibition. The greater benefit of the combination therapy was suggested in a subgroup analysis of the CheckMate 649 trial,8 since among 44 patients with dMMR/MSI-H tumors who were randomized to receive nivolumab plus chemotherapy, the median OS was of 38.7 months versus 12.3 months among the patients submitted to chemotherapy alone (HR: 0.38; 95%CI: 0.17-0.84), and the benefit was even greater in the subgroup of patients with CPS ≥ 5 and dMMR (median OS: 44.8 months versus 8.8 months; HR: 0.32).

As with the first-line therapy, the second-line therapy also aims to control symptoms and increase survival. For patients with dMMR/MSI-H GEA, pembrolizumab remains as an option if it has not been administered as the first-line therapy. It has been subsequently established10 that immune checkpoint inhibition appears to benefit a subset of patients with dMMR tumors, regardless of the anatomical site of origin or tissue histology. Therefore, in 2017, the FDA approved pembrolizumab for the treatment of advanced solid tumors that harbor dMMR/MSI-H and have progressed after the first-line treatment (treatment-agnostic approval).

Between 5% and 19% of gastric adenocarcinomas have high levels of TMB, which represents the number of mutations per megabase (mut/Mb) harbored by tumor cells.10 It appears to be an independent biomarker of benefit for immunotherapy if TMB ≥ 10 mut/Mb after progression while on standard regimens. In the phase-II KEYNOTE-158 study,10 which enrolled 24 GC patients, there were 11 objective responses (45.8%), 4 of which were complete, and the median PFS was of 11 months.

New diagnostic techniques have contributed to the characterization of the genetic profile of GC and to the identification of new potential molecular targets. Claudin 18.2, a component of intercellular junctions, is commonly expressed in multiple cancers, including GC, and is not expressed in any healthy tissues, apart from the gastric mucosa. Zolbetuximab, an experimental monoclonal antibody that targets claudin 18.2, was evaluated in combination with oxaliplatin-based chemotherapy in the SPOTLIGHT19 and GLOW20 trials and demonstrated an improvement in survival (18.2 versus 15.5 months; HR: 0.750; p = 0.0053; and 14.3 versus 12.1 months; HR: 0.771; p = 0.0118 respectively) in the population of patients with locally-advanced or unresectable, HER2-negative, treatment-naïve GC.

Inhibition of the vascular endothelial growth factor (VEGF) receptor (VEGFR) reduces tumor growth and vascularization.21 The benefit of bevacizumab (a monoclonal antibody that binds to soluble VEGF and prevents binding to VEGFR) for gastric adenocarcinomas and GEAs is uncertain. An improvement in survival after adding bevacizumab to capecitabine plus cisplatin could not be shown in the global phase-III AVAGAST trial.22

Ramucirumab is a recombinant monoclonal antibody that binds to VEGF receptor 2 (VEGFR2), blocking receptor activation. At least two trials, REGARD23 e RAINBOW,24 demonstrated an improvement in survival with the ramucirumab therapy, either as a monotherapy or in combination with paclitaxel in patients with previously-treated advanced GEA. Folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus ramucirumab is a reasonable alternative to ramucirumab plus paclitaxel.25 Additionally, results from the phase-III INTEGRATE IIa study26 presented at the ASCO 2023 Gastrointestinal Cancers Symposium showed that regorafenib significantly improved OS (4.5 months versus 4.0 months; HR: 0.70; 95%CI: 0.53–0.92) in patients under later-line treatment for advanced GEA.

Different types of agents targeting fibroblast growth factor receptors (FGFRs) have been explored, however, without robust clinical evidence. Bemarituzumab has shown some promising results as the first-line treatment for metastatic GC. The phase-II FIGHT study27 was designed to evaluate the efficacy of the bemarituzumab plus oxaliplatin-based chemotherapy regimen and demonstrated a 2-month improvement in PFS (9.5 months in the bemarituzumab group and 7.4 months in the placebo group; HR: 0.68; 95%CI: 0.44–1.04).

Activation of the MET proto-oncogene pathway is associated with tumor invasiveness and poor disease prognosis. The anti-MET monoclonal antibody onartuzumab was studied in combination with FOLFOX versus placebo plus FOLFOX in metastatic HER2-negative GEA patients, and the addition of anti-MET did not improve the outcomes in the general population or in MET-positive patients identified by through immunohistochemistry.28 Rilotumumab, a fully-humanized monoclonal antibody that neutralizes the hepatocyte growth factor (HGF), thus preventing MET activation, was also studied in association with chemotherapy in the same patient profile, and neither was it effective in improving results.29 30 31

The phase-III STAR-221 trial40 evaluated the safety and efficacy of various combinations of anti-T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (anti-TIGIT; domvanalimab) and anti-PD-1 (zimberelimab) monoclonal antibodies in patients with unresectable or metastatic locally-advanced GEA (Table 2). The combination of domvanalimab and zimberelimab with FOLFOX achieved an 80% ORR in patients with positive PD-L1 (tumor positivity area ≥ 5%).

Neurotrophic tropomyosin-related kinase (NTRK) gene fusions (NTRK1, NTRK2, and NTRK3) lead to the expression of constitutively-active chimeric tropomyosin receptor kinase (TRK) proteins (TRKA, TRKB, and TRKC), which act as potential oncogenic drivers across various types of tumors. In GC, NTRK fusions are exceedingly rare, but they may indicate an aggressive phenotype. Larotrectinib and entrectinib, both TRK inhibitors, have shown remarkable efficacy against NTRK fusion-positive tumors, regardless of tumor type (“tumor-agnostic”).33 In 2018, the FDA approved larotrectinib for the treatment of solid tumors with NTRK gene fusions in adult and pediatric patients, based on data from three multicenter clinical trials.34 These trials treated 55 patients with metastatic or unresectable solid tumors harboring NTRK gene fusions, achieving a 75% ORR with a complete response rate of 22%.34 In 2019, entrectinib received FDA approval for the same indications, supported by data from three clinical trials35 involving 54 treated patients, demonstrating an ORR of 57% with a complete response rate of 7%. Both drugs have shown durable and clinically-significant responses with manageable safety profiles, making them recommended second-line or subsequent treatment options for patients with gastric tumors positive for NTRK gene fusions.

Substantial advances have been made in the treatment of GC; however, more research is needed to optimize treatment strategies. For patients with gastric adenocarcinoma who do not overexpress HER2 and are not candidates for immunotherapy (CPS < 5–low or absent PD-L1 expression), the choice should be a dual classic combination containing platinum and fluoropyrimidine (such as FOLFOX or CapOX).

Phase-III studies on second-line metastatic therapy showed that paclitaxel, docetaxel, and irinotecan increase OS in relation to clinical support, with similar results. One of these studies36 included 202 patients and compared second-line chemotherapy (docetaxel or irinotecan) versus best supportive care. The median OS favored the chemotherapy arm (5.3 versus 3.8 months; HR: 0.65; p = 0.007), with no difference observed between docetaxel and irinotecan (OS of 5.2 versus 6.5 months; p = 0.116).36

The combination of trifluridine and tipiracil hydrochloride forms TAS-102, an oral agent that is an option for third-line or subsequent therapy in patients who maintain good performance status after undergoing treatment with two or more agents. The effectiveness of the regimen was suggested in the TAGS trial.37 In this study with 507 heavily-pretreated GEA patients (more than 60% in each group had previously received 3 or more chemotherapy regimens), TAS-102 significantly improved OS relative to placebo (median: 5.7 versus 3.6 months) and was reasonably well tolerated.37